A major theme of this year’s AACR meeting examines the approaches that aim to further improve the anti-tumour efficacy of anti-PD-1 and –PD-L1 checkpoint inhibitors (CPIs) in the clinic. CPIs have dramatically revolutionised conventional treatment paradigms in “hot” or “inflamed” cancers such as melanoma, bladder and non-small cell lung cancer (NSCLC) where treatment with a single agent CPI provides substantially higher clinical benefit over the established standard of care regimens.

On the other hand, the efficacy of single-agent CPIs, as well as their combination with an anti-CTLA-4 CPI, has so far been limited in “cold” tumours such as pancreatic ductal adenocarcinoma (PDAC), glioblastoma, ovarian, and prostate cancer. Both of the CPI mechanisms boost anti-tumour immunity by promoting the expansion of and relieving tumour cell and microenvironment (TME)-mediated suppression of cytotoxic T lymphocytes (CTLs).

While these mechanisms are sufficient in the so-called “hot” or “inflamed” tumors, which are infiltrated with immune cells, “cold” tumors where CTLs are excluded from the TME are more resistant to the therapeutic approaches which rely on the sole activation of CTLs and may require complementary immuno-modulation of the TME alongside treatment with anti-PD-1/-PD-L1/-CTLA-4 CPIs for efficient CTL recruitment, activation, and subsequent therapeutic efficacy.

Treating “cold” tumours

One of the distinguishing features of PDAC is the extensive tumour stroma that surrounds the tumour cells and constitutes approximately up to 80% of the tumour mass in PDAC.

Stromal elements such as immunosuppressive T regulatory cells, myeloid-derived suppressor cells and tumour-associated macrophages (TAMs) collectively contribute to the scarcity of CTLs and dendritic immune effector cells within a tumour, generating a TME that is highly immunosuppressive and resistant to standard therapies. Therefore, it is perhaps not surprising that treatment with CPIs will not be a viable strategy on their own in a tumour environment that is not accessible to CTLs. To this end, one of the exciting strategies presented at the AACR is coupling CD40 agonists with anti-PD-1/PD-L1 CPIs.

CD40 is a member of the tumour necrosis factor receptor superfamily and is broadly expressed by immune cells, in particular B lymphocytes, dendritic cells, and macrophages. Signalling via CD40 induces maturation of dendritic cells, which have a crucial role in activating CTLs. In mouse models of PDAC, treatment with an agonist CD40 antibody (Ab) is associated with massive influx of CTLs into PDAC tumours and subsequent tumour regression.

In addition, TAMs isolated from PDAC tumours following treatment with the CD40 Ab are activated and capable of recognising and lysing tumour cells. The dual effect of CD40 agonists is therefore highly relevant in the context of PDAC. The T-cell-independent mechanism of action (MoA) of the CD40 immunotherapy, via activation of TAMs in the TME would serve to convert the “cold” TME in PDAC to an “inflamed” one, which would then become accessible to CTLs and therefore be expected to become more responsive to treatment with CPIs. Meanwhile, the T-cell dependent MoA of the CD40 immunotherapy would further potentiate the effect of CPIs on CTLs.

Ongoing trials of CD40 agonists

CD40 agonists have demonstrated synergistic activity in combination with gemcitabine in patients with treatment-naïve PDAC and resulted in complete tumour regression in preclinical models when paired with an anti-PD-1 and/or anti-CTLA-4 CPI. Currently, an ongoing Phase I/II trial (NCT03214250) conducted by Parker Institute for Cancer Immunotherapy in collaboration with Bristol-Myers Squibb and Apexigen is evaluating the efficacy of the triple combination regimen of Apexigen’s CD40 agonist APX005M, gemcitabine and Celgene’s Abraxane (nab-paclitaxel) with and without BMS’ anti-PD-1 Opdivo (nivolumab) in treatment-naïve metastatic PDAC.

In addition, Roche is evaluating the combination of the in-house CD40 agonist selicrelumab (RG7876) and the anti-PD-L1 Tecentriq (atezolizumab) in solid tumors in a Phase I clinical trial (NCT02304393). Despite the scarcity of late stage clinical studies, positive results from these two trials could spur further interest in CD40 agonists and bring them to the forefront in the immuno-oncology space alongside anti-PD-1/PD-L1/CTLA-4 CPIs.

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